Perturbed cell signaling network and suicide neurobiology

扰动的细胞信号网络和自杀神经生物学

基本信息

批准号：
8908050
负责人：
Yogesh Dwivedi
金额：
$ 33.08万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-12 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8908050
关键词：
70-kDa Ribosomal Protein S6 Kinases Acetylation Affinity Apoptosis Apoptotic Area Attention Autopsy BDNF gene Behavioral Brain Brain region Brain-Derived Neurotrophic Factor CREB1 gene Caliber Cause of Death Cell Nucleus Cell Survival Cerebellum Characteristics Cleaved cell Clinical Cytosol DNA Fragmentation Dendrites Depressed mood Disease susceptibility FOS gene Family history of Functional disorder Gene Expression Genes Genetic Genetic Transcription Health Hippocampus (Brain)Histones Intervention JUN gene Lead Length Link MAPK3 gene MAPK8 gene Major Depressive Disorder Mediating Mitogen-Activated Protein Kinases Mitogens Modification Molecular Morphology NGFR Protein NTRK2 gene Neurobiology Neuronal Plasticity Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Nuclear Pathway interactions Peripheral Personality Phosphatidylinositols Phosphorylation Phosphotransferases Play Polyribosomes Prefrontal Cortex Prevalence Prevention approach Proteins Psychiatric Diagnosis Public Health RPS6KA gene Reporting Ribosomal Protein S6 Kinase Role Sampling Scaffolding Protein Signal Pathway Signal Transduction Signal Transduction Pathway Site Stress Suicide Suicide attempt Suicide prevention Surface Synapses System Tail TdT-Mediated dUTP Nick End Labeling Assay Testing Therapeutic Intervention Tissues To specify Transactivation Translations United States Vertebral column activating transcription factor 1 age group base caspase-3 chromatin immunoprecipitation chromatin remodeling density design eIF-4B genetic regulatory protein human FRAP1 protein mRNA capping neuron apoptosis neurotrophic factor novel overexpression postsynaptic protective effect psychologic psychosocial relating to nervous system scaffold suicidal behavior suicide brain trait transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Suicide is a major public health concern. Suicidal behavior occurs in the context of a diathesis that is characterized by traits in multiple domains: behavioral, clinical, personality, and biologic. While the complexity of suicidal behavior requires a multi-faceted prevention approach, the identification of neurobiological dysfunction is critical for the pharmacological interventions that may have protective effects against suicidal behavior. In this context, we have shown reduced BDNF gene expression and less activation of its cognate receptor TrkB in the brain of suicide subjects. In addition, we have found that p75NTR, a low affinity BDNF receptor is upregulated in the brain of these subjects. BDNF, which plays a critical role in neural plasticity and cell survival, essentially mediates its action via TrkB-mediated activation of extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide 3 kinase (PI3K) signaling pathways. Abnormalities in these two signaling systems at the upstream levels were also found in the same brain areas of suicide subjects in which abnormalities were noted in BDNF/TRKB/p75NTR. These changes were present in all suicide subjects regardless of psychiatric diagnosis. To better understand the functional significance of altered BDNF signaling at molecular and cellular levels and their implications in the neurobiology of suicide, we propose to test the hypothesis that hypoactive BDNF/TrkB-mediated ERK1/2 and PI3K/Akt and overexpressed p75NTR will lead to modifications in the interaction and activation of downstream scaffolding/regulatory proteins, translational machinery, chromatin remodeling, and structural plasticity in the suicide brain. To test our hypothesis, in brain areas implicated in suicidal behavior, i.e., dlPFC and hippocampus (cerebellum as negative control brain region) from well-characterized and well-matched depressed suicide and non-psychiatric control subjects (n = 30 in each group), we aim to examine whether: 1) hypoactive ERK1/2 will lead to altered activation of substrates p90 ribosomal S6 kinase (RSK) and mitogen- and stress-activated kinase (MSK) and their mediated transactivation of transcription factors and chromatin remodeling; 2) hypoactive ERK1/2 and PI3K will lead to less active translational machinery, translation of postsynaptic genes, and altered dendritic morphology; and 3) altered PI3K/Akt and p75NTR will be associated with altered interactions of scaffolding proteins leading to c-Jun kinase (JNK) activation and altered expression and functional characteristics of downstream apoptotic regulatory proteins and neuronal apoptosis. To make sure that the effects are suicide specific, we will perform these studies in the same brain areas of an additional group of well-matched subjects who were depressed (no previous suicide attempt and no family history of suicide) and died by causes other than suicide (n = 30). Our proposed study will precisely and mechanistically assess the complexity of cellular signaling at the molecular, cellular, and functional levels in suicide brain and will have a significant impact in understanding not only the neurobiological basis of suicide but in designing more efficacious treatment strategies.

描述（由申请人提供）：自杀是一个主要的公共卫生问题。自杀行为发生在具有多个领域特征的背景下：行为、临床、人格和生物学。虽然自杀行为的复杂性需要作为一种多方面的预防方法，神经生物学功能障碍的识别对于可能对自杀行为产生保护作用的药物干预至关重要。在这种情况下，我们发现自杀受试者大脑中 BDNF 基因表达减少，其同源受体 TrkB 激活减少。此外，我们发现 p75NTR（一种低亲和力 BDNF 受体）在这些受试者的大脑中表达上调。 BDNF 在神经可塑性和细胞存活中发挥着关键作用，主要通过 TrkB 介导的细胞外信号调节激酶 (ERK)1/2 和磷酸肌醇 3 激酶 (PI3K) 信号通路的激活来介导其作用。在自杀受试者的相同大脑区域中也发现了上游水平的这两个信号系统的异常，其中 BDNF/TRKB/p75NTR 出现异常。无论精神病学诊断如何，所有自杀受试者都存在这些变化。为了更好地理解分子和细胞水平上 BDNF 信号传导改变的功能意义及其对自杀神经生物学的影响，我们建议检验以下假设：BDNF/TrkB 介导的 ERK1/2 和 PI3K/Akt 活性低下以及 p75NTR 过度表达将导致自杀自杀大脑中下游支架/调节蛋白的相互作用和激活、翻译机制、染色质重塑和结构可塑性的改变。为了检验我们的假设，在与自杀行为有关的大脑区域，即 dlPFC 和海马体（小脑作为阴性对照大脑区域），来自特征明确且匹配良好的抑郁症自杀者和非精神病对照受试者（每组 n = 30），我们的目的是检查：1) ERK1/2 活性低下是否会导致底物 p90 核糖体 S6 激酶 (RSK) 的激活发生改变，以及丝裂原激活激酶和应激激活激酶 (MSK) 及其介导的转录因子反式激活和染色质重塑； 2）ERK1/2和PI3K活性低下将导致翻译机制、突触后基因翻译和树突形态改变的活性降低； 3) PI3K/Akt 和 p75NTR 的改变与支架蛋白相互作用的改变有关，导致 c-Jun 激酶 (JNK) 激活，并改变下游凋亡调节蛋白和神经元凋亡的表达和功能特征。为了确保效果是针对自杀的，我们将在另一组匹配良好的受试者的相同大脑区域中进行这些研究，这些受试者患有抑郁症（以前没有自杀企图，也没有自杀家族史），并且死于除以下原因之外的原因：自杀（n = 30）。我们提出的研究将在分子、细胞和功能水平上精确地、机械地评估自杀大脑中细胞信号传导的复杂性，并将对理解自杀大脑产生重大影响。自杀的神经生物学基础，但设计更有效的治疗策略。